FDA Approves TABRECTA (Capmatinib) for Treatment of Adult Patients with Metastatic Non-small Cell Lung Cancer

FDA Approves TABRECTA (Capmatinib) for Treatment of Adult Patients with Metastatic Non-small Cell Lung Cancer

On May 6, 2020, the U.S. Food and Drug Administration (FDA) approved TABRECTA (capmatinib) for treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

The approved recommended dosage of TABRECTA is 400 mg orally twice daily with or without food. Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as important warnings and precautions about interstitial lung disease/pneumonitis, hepatotoxicity, risk of photosensitivity, or embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

• MOA: Capmatinib is a kinase inhibitor that targets MET, including the mutant variant produced by exon 14 skipping.
• General PK: Capmatinib exposure (AUC_0-12h and C_max) increased approximately proportionally over a dose range of 200 mg (0.5 times the recommended dosage) to 400 mg. Capmatinib reached steady-state by day 3 following twice daily dosing, with a mean (% coefficient of variation [%CV]) accumulation ratio of 1.5 (41%).
• Absorption: After administration of TABRECTA 400 mg orally in patients with cancer, capmatinib peak plasma concentrations (C_max) were reached in approximately 1 to 2 hours (T_max). The absorption of capmatinib after oral administration is estimated to be greater than 70%.
• Distribution: The apparent mean volume of distribution at steady-state is 164 L. Capmatinib plasma protein binding is 96%, independent of capmatinib concentration. The blood-to-plasma ratio was 1.5, but decreased at higher concentrations to 0.9.
• Elimination: The effective elimination half-life of capmatinib is 6.5 hours. The mean (%CV) steady-state apparent clearance of capmatinib is 24 L/hr (82%).
• Metabolism: Capmatinib is primarily metabolized by CYP3A4 and aldehyde oxidase.
• Excretion: Following a single oral administration of radiolabeled-capmatinib to healthy subjects, 78% of the total radioactivity was recovered in feces with 42% as unchanged and 22% was recovered in urine with negligible as unchanged.

Drug Interactions

• Strong CYP3A Inhibitors: Closely monitor patients for adverse reactions during coadministration of TABRECTA with strong CYP3A inhibitors. Coadministration of TABRECTA with a strong CYP3A inhibitor increased capmatinib exposure, which may increase the incidence and severity of adverse reactions of TABRECTA.
• Strong and Moderate CYP3A Inducers: Avoid coadministration of TABRECTA with strong or moderate CYP3A inducers. Coadministration of TABRECTA with a strong or moderate CYP3A inducer decreased capmatinib exposure, which may decrease TABRECTA anti-tumor activity.
• CYP1A2 Substrates: If coadministration is unavoidable between TABRECTA and CYP1A2 substrates where minimal concentration changes may lead to serious adverse reactions, decrease the CYP1A2 substrate dosage in accordance with the approved prescribing information. Coadministration of TABRECTA increased the exposure of a CYP1A2 substrate, which may increase the adverse reactions of these substrates.
• P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) Substrates: If coadministration is unavoidable between TABRECTA and P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions, decrease the P-gp or BCRP substrate dosage in accordance with the approved prescribing information. Coadministration of TABRECTA increased the exposure of a P-gp substrate and a BCRP substrate, which may increase the adverse reactions of these substrates.
• MATE1 and MATE2K Substrates: If coadministration is unavoidable between TABRECTA and MATE1 or MATE2K substrates where minimal concentration changes may lead to serious adverse reactions, decrease the MATE1 or MATE2K substrate dosage in accordance with the approved prescribing information. Coadministration of TABRECTA may increase the exposure of MATE1 and MATE2K substrates, which may increase the adverse reactions of these substrates.

Use in Specific Populations

No clinically significant effects on the pharmacokinetic parameters of capmatinib were identified for the following covariates assessed: age (26 to 90 years), sex, race (White, Asian, Native American, Black, unknown), body weight (35 to 131 kg), mild to moderate renal impairment (baseline CLcr 30 to 89 mL/min by Cockcroft-Gault) and mild, moderate or severe hepatic impairment (Child-Pugh classification).

• Renal Impairment: No dosage adjustment is recommended in patients with mild (baseline creatinine clearance [CLcr] 60 to 89 mL/min by Cockcroft-Gault) or moderate renal impairment (CLcr 30 to 59 mL/min). TABRECTA has not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min).
• Lactation: Advise women not to breastfeed during treatment with TABRECTA and for 1 week after the last dose because of the potential for serious adverse reactions in breastfed children. There are no data on the presence of capmatinib or its metabolites in either human or animal milk or its effects on the breastfed child or on milk production.

Efficacy and Safety

Efficacy of TABRECTA was demonstrated in a multicenter, non-randomized, open-label, multi-cohort study that enrolled patients with NSCLC with a mutation that leads to MET exon 14 skipping, epidermal growth factor receptor wild-type and anaplastic lymphoma kinase negative status, and at least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The major efficacy outcome measure was overall response rate (ORR) as determined by a Blinded Independent Review Committee according to RECIST 1.1. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 20%) are peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite.

Full prescribing information is available at https://go.usa.gov/xvHp6. Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C. Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at https://www.fda.gov/safety/medwatch/default.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). For information on the COVID-19 pandemic, see the following resources: FDA: Coronavirus Disease 2019 (COVID-19) NCI: Coronavirus: What People With Cancer Should Know CDC: Coronavirus (COVID-19) The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at https://updates.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs. We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.